Divergent adaptive immune responses define two types of long COVID.

Background: The role of adaptive immune responses in long COVID remains poorly understood, with contrasting hypotheses suggesting either an insufficient antiviral response or an excessive immune response associated with inflammatory damage. To address this issue, we set to characterize humoral and CD4+ T cell responses in long COVID patients prior to SARS-CoV-2 vaccination. Methods: Long COVID patients who were seropositive (LC+, n=28) or seronegative (LC-, n=23) by spike ELISA assay were recruited based on (i) an initial SARS-CoV-2 infection documented by PCR or the conjunction of three major signs of COVID-19 and (ii) the persistence or resurgence of at least 3 symptoms for over 3 months. They were compared to COVID patients with resolved symptoms (RE, n=29) and uninfected control individuals (HD, n=29). Results: The spectrum of persistent symptoms proved similar in both long COVID groups, with a trend for a higher number of symptoms in the seronegative group (median=6 vs 4.5; P=0.01). The use a highly sensitive S-flow assay enabled the detection of low levels of SARS-CoV-2 spike-specific IgG in 22.7% of ELISA-seronegative long COVID (LC-) patients. In contrast, spike-specific IgG levels were uniformly high in the LC+ and RE groups. Multiplexed antibody analyses to 30 different viral antigens showed that LC- patients had defective antibody responses to all SARS-CoV-2 proteins tested but had in most cases preserved responses to other viruses. A sensitive primary T cell line assay revealed low but detectable SARS-CoV-2-specific CD4 responses in 39.1% of LC- patients, while response frequencies were high in the LC+ and RE groups. Correlation analyses showed overall strong associations between humoral and cellular responses, with exceptions in the LC- group. Conclusions: These findings provide evidence for two major types of antiviral immune responses in long COVID. Seropositive patients showed coordinated cellular and humoral responses at least as high as those of recovered patients. In contrast, ELISA-seronegative long COVID patients showed overall low antiviral responses, with detectable specific CD4+ T cells and/or antibodies in close to half of patients (52.2%). These divergent findings in patients sharing a comparable spectrum of persistent symptoms raise the possibility of multiple etiologies in long COVID.

Depressive symptoms after hepatitis C cure and socio-behavioral correlates in aging people living with HIV (ANRS CO13 HEPAVIH).

Background & Aims: A growing literature shows an improvement of chronic hepatitis C virus (HCV)-related depression after successful treatment with direct-acting antivirals. However, depression after HCV cure remains insufficiently documented in people living with HIV (PLWH) and HCV, a population with specific mental health challenges. This study aimed to (i) document the prevalence of moderate-to-severe depression (PHQ-9 score ≥10) across different age classes in HCV-cured PLWH; (ii) identify associated socio-behavioral correlates. Methods: Descriptive analyses were performed on data collected during a cross-sectional survey (February 2018 - May 2019) nested in a prospective, multicenter cohort of individuals living with HIV and HCV (ANRS CO13 HEPAVIH). Socio-behavioral correlates of moderate-to-severe depression were identified using logistic regression. Results: Among the 398 HCV-cured individuals in the study sample (median age [IQR]: 56 [53-59] years; 73.1% men), 23.9% presented with moderate-to-severe depression (PHQ-9 score ≥10). Depressive symptom prevalence rates were as follows: anhedonia: 52.3%; feeling 'down' or feelings of hopelessness: 48.3%; sleeping problems: 65.7%; lack of energy: 70.3%; eating disorders: 51.2%; lack of self-esteem: 34.3%; difficulty concentrating: 34.9%; sluggishness (in movement and voice) or restlessness: 24.6%; suicidal ideation: 17.1%. No significant difference was detected across age classes. Female sex, unhealthy alcohol use, sedentary lifestyle, and unhealthy eating behaviors were associated with increased odds of moderate-to-severe depression. Conclusions: Depressive symptoms were common in this sample of HCV-cured PLWH. Unlike findings for the French general population, the prevalence of depression did not decrease with age class. Mental health remains a key issue for HIV-HCV-coinfected individuals, even after HCV cure, especially in women and in individuals with unhealthy behaviors. Lay summary: Despite potential improvements in mental health after successful treatment with direct-acting antivirals, many people living with HIV (PLWH) and hepatitis C virus (HCV) - even in older age classes - still face depressive symptoms after HCV cure. In this population, women and people reporting unhealthy alcohol use, sedentary lifestyle, or unhealthy eating behaviors are more prone to report depressive symptoms after HCV cure. Mental health and lifestyle-related issues should be integrated in a global care model for PLWH living with or having a history of hepatitis C.

Sustained virological response after treatment with direct antiviral agents in individuals with HIV and hepatitis C co-infection.

INTRODUCTION: Randomized trials and observational studies have consistently reported rates of sustained virological response (SVR), equivalent to hepatitis C virus (HCV) cure, as high as 95% following treatment with direct-acting antiviral (DAA) treatment in individuals with HIV and HCV co-infection. However, large studies assessing whether SVR rates differ according to demographic and clinical strata are lacking. Additionally, the SVR rates reported in the literature were typically computed in non-random samples of individuals with available post-DAA HCV-RNA measures. Here, we aimed to estimate the probability of SVR after DAA treatment initiation in persons with HIV and HCV co-infection overall and by demographic and clinical characteristics with and without adjustment for missing HCV-RNA testing. METHODS: We included adults with HIV-HCV co-infection who received DAA treatment between 2014 and 2020 in HepCAUSAL, an international collaboration of cohorts from Europe and North America. We estimated the proportions of DAA recipients who had documented SVR (defined as an undetectable HCV-RNA at least 12 weeks after the end of DAA treatment) overall and by strata defined by age, sex, presence of cirrhosis, calendar period, mode of HIV acquisition, CD4 cell count and HCV genotype at DAA treatment. We then compared these rates with those obtained using the parametric g-formula to impute SVR status for individuals with no SVR assessment. RESULTS AND DISCUSSION: A total of 4527 individuals who initiated DAA treatment (88% males, median [IQR] age 56 [50, 62] years) were included. Of the total of 642 (14%) individuals had no HCV-RNA test on or after 12 weeks after the end of treatment. The overall observed and g-formula imputed SVR rates were 93% (95% CI 93, 94) and 94% (95% CI 92, 95), respectively. SVR estimates were similarly high across all strata. A substantial proportion of individuals who received DAA treatment were never assessed for SVR post-DAA and strategies for more systematic routine HCV-RNA testing should be considered. CONCLUSIONS: Our estimates with and without adjustment for missing HCV-RNA testing indicate SVR rates of approximately 95%, like those reported in clinical trials.

Cannabis Use as a Protective Factor Against Overweight in HIV-Hepatitis C Virus Co-Infected People (ANRS CO13 HEPAVIH Cohort).

Overweight is increasingly prevalent in people living with HIV (PLWH), and is a high risk factor for metabolic disorders in this population. PLWH co-infected with hepatitis C virus (HCV) have a higher risk of metabolic disorders than their mono-infected counterparts. The putative relationship between cannabis use and body weight found in the general population has never been documented in HIV-HCV co-infected people. We tested whether cannabis use is associated with body mass index (BMI), overweight, and underweight in HCV co-infected PLWH (N = 992). Mixed-effects linear and logistic regression models were used to study the association between cannabis use and the three outcomes over time. After multivariable adjustment, cannabis use was inversely associated with BMI. Cannabis use was associated with a lower and higher risk of overweight and underweight, respectively. Cannabis use should be assessed and taken into account in the clinical management of the HIV-HCV co-infected population.

Smoking increases the risk of post-acute COVID-19 syndrome: Results from a French community-based survey.

INTRODUCTION: We aimed to estimate the prevalence and incidence of specific symptoms and predictors of post-acute COVID-19 syndrome using data collected from an anonymous online survey. METHODS: We included adult participants with symptoms ≥60 days (D60+), fulfilling the World Health Organization COVID-19 cases definition, and/or hospitalized for COVID-19 at the time of infection (D0). Self-reported symptoms were collected at D0 and D60+. Logistic regression was performed to identify factors associated with self-reported cutaneous signs prevalence and self-reported tachycardia and/ or HBP incidence on D60+. RESULTS: From April to June 2020, 956 members of a Twitter long-term COVID-19 community were included in the study population: 81% were women, 81% were aged <50 year, 22% were smokers, and 95% have never been hospitalized. At D60+, the 956 participants reported a broad spectrum of symptoms which were also present at D0+. At D60+, 16% and 39% of participants reported cutaneous signs and tachycardia and/or hypertension, respectively. The incidence of self-reported tachycardia and/or hypertension at D60+ was 12%. Female gender (AOR=2.56; 95% CI: 1.22-6.1) and smoking (AOR=2.34; 95% CI: 1.39-3.92) were associated with prevalence of cutaneous signs at D60+. Smoking (AOR=2.05; 95% CI: 1.2- 3.47) was the main correlate of tachycardia and/or HBP incidence at D60+. CONCLUSIONS: The incidence of self-reported tachycardia and/or hypertension is not negligible and suggests an interaction between COVID-19 and smoking. Reinforcing symptoms monitoring of people after acute COVID-19, mainly women and smokers, and expanding the promotion of smoking cessation strategies are novel priorities in this COVID-19 era.

HCV cure: an appropriate moment to reduce cannabis use in people living with HIV? (ANRS CO13 HEPAVIH data).

BACKGROUND: Thanks to direct-acting antivirals, hepatitis C virus (HCV) infection can be cured, with similar rates in HCV-infected and HIV-HCV co-infected patients. HCV cure is likely to foster behavioral changes in psychoactive substance use, which is highly prevalent in people living with HIV (PLWH). Cannabis is one substance that is very commonly used by PLWH, sometimes for therapeutic purposes. We aimed to identify correlates of cannabis use reduction following HCV cure in HIV-HCV co-infected cannabis users and to characterize persons who reduced their use. METHODS: We used data collected on HCV-cured cannabis users in a cross-sectional survey nested in the ANRS CO13 HEPAVIH cohort of HIV-HCV co-infected patients, to perform logistic regression, with post-HCV cure cannabis reduction as the outcome, and socio-behavioral characteristics as potential correlates. We also characterized the study sample by comparing post-cure substance use behaviors between those who reduced their cannabis use and those who did not. RESULTS: Among 140 HIV-infected cannabis users, 50 and 5 had reduced and increased their use, respectively, while 85 had not changed their use since HCV cure. Cannabis use reduction was significantly associated with tobacco use reduction, a decrease in fatigue level, paying more attention to one's dietary habits since HCV cure, and pre-HCV cure alcohol abstinence (p = 0.063 for alcohol use reduction). CONCLUSIONS: Among PLWH using cannabis, post-HCV cure cannabis reduction was associated with tobacco use reduction, improved well-being, and adoption of healthy behaviors. The management of addictive behaviors should therefore be encouraged during HCV treatment.

Visual interpretation of brain hypometabolism related to neurological long COVID: a French multicentric experience.

BACKGROUND: This multicentre study aimed to provide a qualitative and consensual description of brain hypometabolism observed through the visual analysis of 18F-FDG PET images of patients with suspected neurological long COVID, regarding the previously reported long-COVID hypometabolic pattern involving hypometabolism in the olfactory bulbs and other limbic/paralimbic regions, as well as in the brainstem and cerebellum. METHODS: From the beginning of August 2021 to the end of October 2021, the brain 18F-FDG PET scans of patients referred for suspected neurological long COVID with positive reverse transcription polymerase chain reaction (RT-PCR) and/or serology tests for SARS-CoV-2 infection were retrospectively reviewed in three French nuclear medicine departments (143 patients; 47.4 years old ± 13.6; 98 women). Experienced nuclear physicians from each department classified brain 18F-FDG PET scans according to the same visual interpretation analysis as being normal, mildly to moderately (or incompletely) affected, or otherwise severely affected within the previously reported long-COVID hypometabolic pattern. RESULTS: On the 143 brain 18F-FDG PET scans performed during this 3-month period, 53% of the scans were visually interpreted as normal, 21% as mildly to moderately or incompletely affected, and 26% as severely affected according to the COVID hypometabolic pattern. On average, PET scans were performed at 10.9 months from symptom onset (± 4.8). Importantly, this specific hypometabolic pattern was similarly identified in the three nuclear medicine departments. Typical illustrative examples are provided to help nuclear physicians interpret long-COVID profiles. CONCLUSION: The proposed PET metabolic pattern is easily identified upon visual interpretation in clinical routine for approximately one half of patients with suspected neurological long COVID, requiring special consideration for frontobasal paramedian regions, the brainstem and the cerebellum, and certainly further adapted follow-up and medical care, while the second half of patients have normal brain PET metabolism on average 10.9 months from symptom onset.

HCV Cure and Cannabis Abstinence Facilitate Tobacco Smoking Quit Attempts in HIV-HCV Co-Infected Patients (ANRS CO13 HEPAVIH Cohort Study).

In Western countries, tobacco smoking is highly prevalent among patients co-infected with HIV and hepatitis C virus (HCV). In the era of antiretrovirals and HCV cure, smoking-related health damages contribute greatly to morbidity and mortality in HIV-HCV co-infected patients. We used longitudinal data from the ANRS CO13 HEPAVIH cohort to identify the correlates of tobacco smoking quit attempts (TSQA) in HIV-HCV co-infected patients. TSQA were modelled using a multivariable discrete-time Cox proportional hazards model in 695 HIV-HCV co-infected tobacco smokers. HCV cure was associated with a 76% higher chance of TSQA (adjusted hazard ratio [95% confidence interval]: 1.76 [1.06-2.93], p = 0.029), and cannabis use with a 37% lower chance (0.63 [0.40-1.00], p = 0.049), independently of the mode of HIV transmission, other psychoactive substance use, and body mass index. Patients should be screened for tobacco and cannabis use at HCV treatment initiation and during follow-up. They should also be provided with comprehensive counselling and referral to addiction services. Non-smoking routes of cannabis administration should be promoted for cannabis users who wish to quit smoking tobacco.

Cannabis use and reduced risk of elevated fatty liver index in HIV-HCV co-infected patients: a longitudinal analysis (ANRS CO13 HEPAVIH).

Background: Cannabis use and elevated fatty liver index (FLI≥ 60) (a biomarker of hepatic steatosis in the general population) have been identified as predictors of HCV-related and overall mortality, respectively, in HIV-HCV co-infected patients. However, the relationship between cannabis use and the risk of elevated FLI has never been explored.Methods: Using five-year follow-up data from 997 HIV-HCV co-infected patients (ANRS CO13 HEPAVIH cohort), we analyzed the relationship between cannabis use and FLI using mixed-effects multivariable logistic (outcome: elevated FLI yes/no) and linear (outcome: continuous FLI) regression models.Results: At the last follow-up visit, 27.4% of patients reported regular or daily cannabis use and 27.8% had elevated FLI. After multivariable adjustment, regular or daily cannabis use was associated with a 55% lower risk of elevated FLI (adjusted odds ratio [95% confidence interval]: 0.45 [0.22; 0.94]; p = 0.033) and lower FLI values (adjusted model coefficient: -4.24 [-6.57; -1.91], p < 0.0001).Conclusions: Cannabis use is associated with a reduced risk of elevated fatty liver index in HIV-HCV co-infected patients. Further research is needed to confirm whether and how cannabinoids may inhibit the development of hepatic steatosis or other metabolic disorders in high-risk populations.

The European Prevalence of Resistance Associated Substitutions among Direct Acting Antiviral Failures.

Background: Approximately 71 million people are still in need of direct-acting antiviral agents (DAAs). To achieve the World Health Organization Hepatitis C elimination goals, insight into the prevalence and influence of resistance associated substitutions (RAS) is of importance. Collaboration is key since DAA failure is rare and real-life data are scattered. We have established a European collaboration, HepCare, to perform in-depth analysis regarding RAS prevalence, patterns, and multiclass occurrence. Methods: Data were extracted from the HepCare cohort of patients who previously failed DAA therapy. Geno-and subtypes were provided by submitters and mostly based on in-house assays. They were reassessed using the Comet HCV subtyping tool. We considered RAS to be relevant if they were associated with DAA failure in vivo previously reported in literature. Results: We analyzed 938 patients who failed DAA therapy from ten different European countries. There were 239 genotypes (GT) 1a, 380 GT1b, 19 GT2c, 205 GT3a, 14 GT4a, and 68 GT4d infections. Several unusual subtypes (n = 15) (GT1b/g/l, GT3b, GT4k/n/r/t) were present. RAS appeared in over 80% of failures and over a quarter had three or more RAS. Multiclass RAS varied over target region and genotype between 0-48%. RAS patterns such as the Q30R + L31M and Q30R + Y93H in GT1a, the L31V + Y93H and L31V + Y93H for GT1b, and A30K + L31M and A30K/V + Y93H for GT3a all occurred with a prevalence below 5%. Conclusion: RAS occur frequently after DAA failures and follow a specific genotype and drug related pattern. Interpretation of the influence of RAS on retreatment is challenging due to various patterns, patients' characteristics, and previous treatment history. Moving towards HCV elimination, an ongoing resistance surveillance is essential to track the presence of RAS, RAS patterns and gather data for a re-treatment algorithm.

Life after hepatitis C cure in HIV-infected people who inject drugs and men who have sex with men treated with direct-acting antivirals in France: Health perceptions and experiences from qualitative and quantitative findings (ANRS CO13 HEPAVIH).

There remains a substantial gap in our understandings of the life experiences of patients following HCV cure among HIV-HCV-co-infected people who inject drugs (PWID) and men who have sex with men (MSM), two key populations targeted for HCV elimination. We described the experiences and perspectives of HIV-positive PWID and MSM, HCV-cured following treatment with direct-acting antivirals (DAA). We used an exploratory sequential mixed approach using both qualitative data (semi-structured interviews with 27 PWID and 20 MSM) and quantitative data (self-administered questionnaires with 89 PWID) via the prospective ANRS CO13 HEPAVIH cohort. PWID reported improvements in physical health-related quality of life (HRQL) and self-reported symptoms following treatment, but no significant change in mental HRQL. During interviews, several MSM, more recently diagnosed with HCV, expressed less concern regarding HCV than HIV infection and interpreted improvements in their overall well-being after HCV cure to be more related to a closer connection with healthcare providers than with viral elimination. By contrast, PWID, particularly those previously exposed to interferon-based treatments, described major improvements in their physical HRQL. Both MSM and PWID reported improvements in cognitive or psychological wellbeing, and a majority of them reported some degree of concern over potential HCV reinfection. To conclude, though health benefits of HCV cure concern both groups, HIV-infected PWID and MSM may have different representations and experiences following DAA treatment, related to their history with HCV. They are thus likely to benefit from holistic, post-treatment follow-up care that is responsive to their evolving health and social contexts.

Coffee Intake and Neurocognitive Performance in HIV/HCV Coinfected Patients (ANRS CO13 HEPAVIH).

Coffee is one of the most consumed beverages worldwide. Previous research has demonstrated its neuroprotective effects in the elderly. People coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) experience an accelerated aging process and cognitive impairment, which significantly impair quality of life and may affect disease-related dimensions such as treatment adherence. This study aimed to analyse the relationship between regular coffee intake and neurocognitive performance (NCP) in HIV-HCV coinfected people. We used data from 139 coinfected patients who participated in both the ANRS CO13 HEPAVIH cohort and the HEPAVIH-Psy cross-sectional survey. Linear regression models adjusting for potential sociodemographic (age, gender, educational level), clinical (liver disease status, ongoing HCV treatment, HIV viral load, major depressive disorder) and socio-behavioural (cannabis use) correlates of NCP were used. Our results showed significant, positive associations between elevated coffee intake (ECI) (three or more cups of coffee per day) and NCP in verbal fluency, psychomotor speed (coding) and executive functioning. ECI might therefore preserve neurocognitive functioning in people living with HIV and HCV.

Self-reported loss of smell without nasal obstruction to identify COVID-19. The multicenter Coranosmia cohort study.

OBJECTIVES: To determine the frequency of SARS-CoV-2 positive samples in a subset of patients consulting for primarily isolated acute (<7 days) loss of smell and to assess the diagnostic accuracy of olfactory/gustatory dysfunction for COVID-19 diagnosis in the overall population tested for COVID-19 in the same period. METHODS: Prospective multicentric cohort study in four olfactory ENT units and a screening center for COVID-19. RESULTS: i) Among a subset of 55 patients consulting for primarily recent loss of smell, we found that 51 (92.7%) had a COVID-19 positive test (median viral load of 28.8 cycle threshold). Loss of smell was mostly total (anosmia), rarely associated with nasal obstruction but associated with a taste disorder in 80%. Olfactory dysfunction occurred suddenly, either as first complaint or preceded by mild symptoms occurring a median of 3 days. The majority of patients (72.9%) partially recovered the sense of smell within 15 days. ii) In a population of 1824 patients tested for COVID-19, the positive predictive value and the specificity of loss of smell and/or taste were 78.5% and 90.3% respectively (sensitivity (40.8%), negative predictive value (63.6%)). CONCLUSIONS: Self-reported loss of smell had a high predictive positive value to identify COVID-19. Making this sign well known publicly could help to adopt isolation measures and inform potential contacts.